Download Phase III trials in oncology: setting standards of care?

VIEWPOINT
www.nature.com/clinicalpractice/onc
Phase III trials in oncology: setting
standards of care?
Siegfried Seeber* and Ada H Braun
S Seeber is the Director
of the West German
Cancer Center, and
AH Braun is a Clinical
Fellow at the West
German Cancer
Center, University
of Duisburg-Essen
Medical School,
Essen, Germany.
AH Braun is also
Research Instructor at
Vanderbilt University,
Nashville, TN, USA.
Correspondence
*West German Cancer
Center
University of DuisburgEssen Medical School
Hufelandstrasse 55
45122 Essen
Germany
[email protected]
Received 17 February 2005
Accepted 14 July 2005
www.nature.com/clinicalpractice
doi:10.1038/ncponc0284
For many years, oncologists worldwide have
advised their patients to enroll in clinical
trials for optimum assessment of treatments,
monitoring and follow-up, and consequently
better survival and quality of life compared
with routine management. Randomized phase
III studies that have survival as the primary
endpoint have been the indisputable basis for
setting new standards and launching new drugs,
combinations and multimodal treatment options
into clinical oncology practice. Such studies may
be misleading, however, when enrolled patients
have not received optimum follow-up therapy
after failure of assigned treatment.
In recent licensing trials for agents targeted
at breast cancer, restricted access to post-study
chemotherapy has yielded ‘superior survival’
data for investigational drug combinations
versus single-agent therapy, with remarkably
poor survival in all cohorts.1 A number of these
trials have resulted in approval of specific regimens. In a study showing ‘superior survival’
for capecitabine plus docetaxel compared with
docetaxel alone (14.5 vs 11.5 months, respectively) in 511 anthracycline-pretreated patients,
only 17% in the docetaxel-alone arm received
post-study capecitabine and overall only 30%
received post-study vinorelbine and 20%
5-fluorouracil.1 Especially given the very short
median times to treatment failure reported
(4.0 and 2.8 months, respectively), it is against
routine practice to offer only two-thirds of
patients third-line chemotherapy. Capecitabine
was consequently registered for breast cancer
therapy, with docetaxel as the mandatory
combination partner.
Gemcitabine was approved for combination
therapy only, because a licensing trial comparing
gemcitabine plus paclitaxel with paclitaxel alone
stated that “gemcitabine plus taxol provides
significant overall survival advantage over
taxol”.2 The advantage of combination over
sequential single-agent therapy is undetermined,
however. Again, unsatisfactory post-study access
to active agents probably accounted for the
426 NATURE CLINICAL PRACTICE ONCOLOGY
unacceptable median survival data reported
(18.5 vs 15 months, respectively).
In a recent randomized trial of trastuzumab plus
docetaxel in 188 patients with HER2-positive metastatic breast cancer, only 48% of the taxotere-alone
control group were documented to receive the
antibody at progress! Yet it was concluded that the
addition of trastuzumab to docetaxel “improves all
clinical outcome parameters, including survival”.3
Would this hold true if patients from the control
group had received vinorelbine plus trastuzumab
after taxotere failure? Albeit active, the latter
combination is still ‘illegal’.
Should such studies set new standards of care
for our patients? For 197 unselected consecutive patients treated in our center in the pretrastuzumab era (between 1 January 1995 and
31 December 1999), the median survival of
breast cancer patients first-line for treatment
of metastatic disease was 36 months, with a
35% 4-year survival (C Pohlkamp, A Welt and S
Seeber, unpublished data). Of 146 patients with
inoperable liver metastases, 25% survived for over
48 months, and 14% for over 60 months—some
for over 8 years. In many cases, clinical responses
were observed even in the sixth or seventh line (see
Supplementary Figure 1 online). These patients
require close monitoring, early intervention at
progression, and individualized multimodal
therapy employing effective drugs either singly
or in adequate combinations, irrespective of their
registration status. Dose-dense regimens should
be used in critical phases and ‘softer’ interims
involving oral maintenance therapy as well as
locoregional treatment options (e.g. surgery,
interventional radiology or hepatic artery infusions). Experienced physicians are not impressed
by studies claiming a survival advantage of 15.4
versus 12.7 months for docetaxel versus paclitaxel
in metastasized breast cancer,4 a result advertised
as a “highlight” of the 2003 ECCO.
In stage IV non-small-cell lung cancer, it took
408 patients to prove that combining paclitaxel
with carboplatin is as effective as vinorelbine
plus cisplatin,5 with equally poor median
SEPTEMBER 2005 VOL 2 NO 9
©2005 Nature Publishing Group
VIEWPOINT
www.nature.com/clinicalpractice/onc
survival (8 months) and 1-year survival rates
(38% vs 36%). In this and a similar ECOG trial
of four two-drug combinations, there was no
routine crossover at treatment failure; nor did
the majority of patients receive adequate secondline or third-line treatment. However, second-line
taxotere can prolong life in platinum-refractory
patients, and third-line irinotecan can induce
significant responses lasting up to 1 year.6
In ovarian cancer, evidence-based medicine
usually favors taxol plus carboplatin as induction
treatment, with topotecan or liposomal doxorubicin for platinum-resistant tumors. Phase
III studies are underway with overall survival as
the primary endpoint.7 Our mono-institutional
analysis involves 77 unselected consecutive
patients with FIGO stage III or IV ovarian carcinoma, who, between 1 January 1993 and 31
December 2003, received an average of six treatment regimens, and early surgical interventions
whenever applicable (C Brinkmann, J Hense
and S Seeber, unpublished data). Therapies were
adjusted on an individualized basis following any
signs of disease progression, producing a median
overall survival of 55 months in the total population and 63 months in stage III patients. Early
adaptation of treatment regimens is mandatory
for good patient outcome, and therapeutic interventions can prolong good-quality survival even
late in the disease course (see Supplementary
Figure 2 online).
Increasing evidence suggests that chemotherapy
in hormone-refractory prostate cancer improves
both quality of life and survival. Tannock et
al.8 examined docetaxel plus prednisone and
mitoxantrone plus prednisone in such patients.
Disconcertingly, they reported “superior survival”
for the docetaxel arm, while crossover therapy
after mitoxantrone failure was documented in
only 20% of patients, with no other follow-up
treatments specified. In our experience, secondline or third-line drugs can induce valuable
responses over several months (A Schneider and
S Seeber, unpublished data) (see Supplementary
Figure 3 online). Hence, the issue is not whether
a mitoxantrone or a taxane-based combination
alone improves patient outcome, but which
combinations or sequences are most rational.
Even colorectal cancer patients have suffered
inferior survival in phase III studies because
of constrained second-line treatment options.
Goldberg et al.9 reported that IFL first-line
therapy was inferior to the FOLFOX regimen, but
most patients enrolled in the study did not receive
second-line oxaliplatin. Tournigand et al.,10
comparing FOLFOX6 followed by FOLFIRI with
the reverse sequence using a crossover design,
found no significant difference in survival.
In conclusion, survival of patients with
common metastatic cancers is determined not
only by the choice of first-line chemotherapy
regimen but also by sequentially applied alternative treatments at progression or relapse.
Phase III trials documenting superior survival
for any given primary chemotherapy in these
diseases often offer patients insufficient access to
salvage treatment and are therefore misleading.
Unfortunately, results emanating from such
studies continue to give rise to restricted
licensing of mandatory drug combinations, even
though physicians need both monotherapeutic
and combined usage of active agents, according
to a patient’s history and preference—especially
in advanced metastatic disease.
Supplementary information is available on the
Nature Clinical Practice Oncology website.
References
1 O’Shaughnessy J et al. (2002) Superior survival with
capecitabine plus docetaxel combination therapy in
anthracycline-pretreated patients with advanced breast
cancer: phase III trial results. J Clin Oncol 20: 2812–2823
2 Albain KS et al. (2004) Global phase III study of
gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as
frontline therapy for metastatic breast cancer (MBC):
First report of overall survival. Proc Am Soc Clin Oncol
22: a510
3 Bell R et al. (2004) Maximizing clinical benefit with
trastuzumab. Semin Oncol 31: 35–44
4 Ravdin P et al. (2003) Phase III comparison of
docetaxel (D) and paclitaxel (P) in patients with
metastatic breast cancer (MBC). Eur J Cancer
Supplements 1: S201
5 Kelly K et al. (2001) Randomized phase III trial of
paclitaxel plus carboplatin versus vinorelbine plus
cisplatin in the treatment of patients with advanced
non-small-cell lung cancer: a Southwest Oncology
Group trial. J Clin Oncol 19: 3210–3218
6 Schneider A et al. (2004) Weekly irinotecan in patients
with advanced non-small-cell lung cancer (NSCLC)
after failure of cisplatin, taxane and gemcitabine based
chemotherapy. Onkologie 27 (suppl 3): aP622
7 Du Bois A et al. (2004) Epirubicin/paclitaxel/carboplatin
(TEC) vs paclitaxel/carboplatin (TC) in first-line treatment
of ovarian cancer (OC) FIGO stages IIB–IV. An AGOGINECO Intergroup phase III trial [abstract]. Proc Am
Soc Clin Oncol 22: a5007
8 Tannock IF et al. (2004) Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate
cancer. N Engl J Med 351: 1502–1512
9 Goldberg RM et al. (2004) A randomized controlled trial
of fluorouracil plus leucovorin, irinotecan, and oxaliplatin
combinations in patients with previously untreated
metastatic colorectal cancer. J Clin Oncol 22: 23–30
10 Tournigand C et al. (2004) FOLFIRI followed by
FOLFOX6 or the reverse sequence in advanced
colorectal cancer: a randomized GERCOR study. J Clin
Oncol 22: 229–237
SEPTEMBER 2005 VOL 2 NO 9
GLOSSARY
ECCO
European Cancer
Conference
ECOG
Eastern Cooperative
Oncology Group
FIGO
International Federation of
Gynecology and Obstetrics
IFL
Also known as the Saltz
regimen; standard therapy
for colorectal cancer
patients consisting of
irinotecan, 5-fluorouracil and
leucovorin
FOLFOX
Chemotherapy regimen for
colorectal cancer patients
consisting of oxaliplatin,
5-fluorouracil and leucovorin
FOLFIRI
A standard chemotherapy
regimen for colorectal
cancer patients consisting
of irinotecan, infusional
5-fluorouracil and leucovorin
Competing interests
The authors declared
they have no competing
interests.
NATURE CLINICAL PRACTICE ONCOLOGY 427
©2005 Nature Publishing Group